The intestine of animals is colonized by a large number of commensal microorganisms that contribute to many host physiological processes. An important role of the intestinal microbiota is to protect the host against colonization and invasio by pathogens that often enter the intestinal tract. However, the interaction between the microbiota and the host immune system that mediates protection against enteric pathogens remains poorly understood. Furthermore, the mechanisms that enteric pathogens employ to overcome the presence of the microbiota remain poorly understood. We find that the commensal microbiota is critical for the elimination of Citrobacter rodentium, an enteric mouse pathogen that models human infection by diarrheagenic enterohemorrhagic (EHEC) and enteropathogenic (EPEC) Escherichia coli. EHEC and EPEC are important causes of watery diarrhea and mortality worldwide. These Gram-negative bacteria are food- and waterborne non-invasive pathogens which attach to and colonize the intestinal tract by inducing characteristic attaching- and-effacing (A/E) lesions on the intestinal epithelium, leading to transient enteritis r colitis in humans. The genome of EPEC and EPEC and related pathogens harbor the locus for enterocyte effacement (LEE) which is critical for bacterial colonization and the ability to cause pathology. LEE virulence factors are controlled by Ler, a transcription factor that acts as a globa regulator of LEE virulence genes. We plan in this proposal to use the Citrobacter rodentium model to test several hypotheses raised by our Preliminary Results. The goal of this proposal is to gain a better understanding of the interactions among the pathogen, the host immune system and the indigenous microbiota that are critical in controlling the colonization and eradication of enteric pathogens. In addition, we propose to develop novel therapeutic strategies to treat C. rodentium-induced colitis based on the ability of the indigenous microbiota to outcompete the pathogen with reduced Ler-mediated virulence. Given that A/E pathogens are a major cause of death and morbidity in human populations, this proposal is expected to have a significant and broad impact in the medical field